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Size-based analysis of fetal DNA fraction in maternal plasma

a fetal dna fraction and plasma technology, applied in the field of size-based analysis of fetal dna fraction in maternal plasma, can solve the problems of inter-individual variation in the level of dna methylation, inability to detect dna methylation markers in the same way for all fetuses, and inability to identify library members. the effect of a single set of genetic markers

Active Publication Date: 2013-09-12
THE CHINESE UNIVERSITY OF HONG KONG
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Benefits of technology

The patent describes methods and systems for estimating the concentration of fetal DNA or tumor DNA in a biological sample, such as maternal plasma or patient's plasma, by measuring the amounts of DNA fragments at various sizes. This is possible because the size of DNA fragments is correlated with the proportion of fetal or tumor DNA. The method uses a computer system to calculate a parameter based on the amounts of DNA fragments at different sizes, and compares it to calibration data points to estimate the fractional concentration of the clinically relevant DNA. The method can be used for analyzing biological samples from organisms, and can help in determining the level of cancer in an individual.

Problems solved by technology

A disadvantage of using genetic markers for the measurement of the fractional fetal DNA concentration is that no single set of genetic markers would be informative for all fetus-mother pair.
The potential disadvantage of the use of DNA methylation markers is that there may be inter-individual variation in the level of DNA methylation.
Furthermore, methods that are used for the detection of DNA methylation markers are typically complex, including the use of methylation-sensitive restriction enzyme digestion (Chan K C A et al.

Method used

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  • Size-based analysis of fetal DNA fraction in maternal plasma
  • Size-based analysis of fetal DNA fraction in maternal plasma
  • Size-based analysis of fetal DNA fraction in maternal plasma

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Embodiment Construction

[0055]It is known that cell-free fetal DNA molecules in maternal plasma are generally shorter than the maternally-derived ones (Chan KCA et al. Clin Chem 2004; 50:88-92; Lo YMD et al. Sci Trans' Med 2010; 2:61ra91). The presence of fetal DNA results in a shift in the overall size distribution of maternal plasma DNA and the degree of shifting is associated with the fractional concentration of fetal DNA. By measuring particular values of the size profile of maternal plasma DNA, embodiments can obtain the fractional fetal DNA concentration in maternal plasma.

[0056]Apart from applications in noninvasive prenatal diagnosis, embodiments can also be used for measuring the fractional concentration of clinically useful nucleic acid species of different sizes in biological fluids, which can be useful for cancer detection, transplantation, and medical monitoring. It has previously been shown that tumor-derived DNA is shorter than the non-cancer-derived DNA in a cancer patient's plasma (Diehl F...

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Abstract

A fractional concentration of clinically-relevant DNA in a mixture of DNA from a biological sample is determined based on amounts of DNA fragments at multiple sizes. For example, the fractional concentration of fetal DNA in maternal plasma or tumor DNA in a patient's plasma can be determined. The size of DNA fragments in a sample is shown to be correlated with a proportion of fetal DNA and a proportion of tumor DNA, respectively. Calibration data points (e.g., as a calibration function) indicate a correspondence between values of a size parameter and the fractional concentration of the clinically-relevant DNA. For a given sample, a first value of a size parameter can be determined from the sizes of DNA fragments in a sample. A comparison of the first value to the calibration data points can provide the estimate of the fractional concentration of the clinically-relevant DNA.

Description

CROSS-REFERENCES TO RELATED APPLICATION[0001]This application is a non-provisional of and claims the benefit of U.S. Provisional Patent Application No. 61 / 608,623, entitled “SIZE-BASED ANALYSIS OF FETAL DNA FRACTION IN MATERNAL PLASMA,” filed on Mar. 8, 2012, and U.S. Provisional Patent Application No. 61 / 621,451, entitled “SIZE-BASED ANALYSIS OF FETAL DNA FRACTION IN MATERNAL PLASMA,” filed on Apr. 6, 2012, which are herein incorporated by reference in its entirety for all purposes.BACKGROUND[0002]The discovery of cell-free fetal DNA in maternal plasma has opened up new possibilities for noninvasive prenatal diagnosis (Lo YMD et al. Lancet 1997; 350:485-487). The mean / median fractional fetal DNA concentration has been reported to be approximately 3% to 10% (Lo YMD et al. Am J Hum Genet 1998; 62:768-775; Lun FMF et al. Clin Chem 2008; 54:1664-1672). The fractional fetal DNA concentration is an important parameter which affects the performance of noninvasive prenatal diagnostic tests...

Claims

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Application Information

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IPC IPC(8): G06F19/22C12Q1/68G16B30/10G16B20/10G16B20/20
CPCG06F19/22C12Q1/6869C12Q2600/112C12Q1/6886G06F19/18G16B20/00G16B20/20G16B20/10G16B30/10C12Q1/6809C12Q1/6827C12Q1/6816G16H50/30G16H50/20C12Q1/6806C12Q2525/204C12Q2537/16C12Q2537/165C12Q2539/107C12Q2545/113C12Q2545/114C12Q2565/137G16H10/40G16B30/00C12Q2535/122
Inventor LO, YUK MING DENNISCHIU, WAI KWUN ROSSACHAN, KWAN CHEEZHENG, WENLIJIANG, PEIYONGLIAO, JIAWEI
Owner THE CHINESE UNIVERSITY OF HONG KONG
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